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. 2023 Jan 9;25(3):436–443. doi: 10.1177/10998004221150395

Exploring the Role of Vitamin D and the Gut Microbiome: A Cross-Sectional Study of Individuals with Irritable Bowel Syndrome and Healthy Controls

Sarah W Matthews 1,✉, Anna Plantinga 2, Robert Burr 1, Kevin C Cain 3, Tor Savidge 4,5, Kendra Kamp 1, Margaret M Heitkemper 1
PMCID: PMC10404909  PMID: 36624571

Abstract

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with multifaceted pathophysiology. Prior studies have demonstrated higher rates of vitamin D deficiency in individuals with IBS compared to healthy controls (HC), as well as associations of vitamin D concentration with IBS symptoms. A systematic review of 10 mouse and 14 human studies reported a positive association between vitamin D (serum levels and supplementation) and beta diversity of gut microbiome in a variety of conditions. The present retrospective case-control study aimed to compare vitamin D (25(OH)D) plasma concentrations and gut microbiome composition in adult women with IBS (n=99) and HC (n=62). Plasma concentrations of 25(OH)D were assessed using the Endocrine Society Guidelines definition of vitamin D deficiency (25(OH)D <20 ng/ml) and insufficiency (25(OH)D >20-<30 ng/ml). 16S rRNA microbiome gene sequencing data was available for 39 HC and 62 participants with IBS. Genus-level Bifidobacterium and Lactobacillus and phylum-level Firmicutes and Bacteroidetes relative abundances were extracted from microbiome profiles. Results showed vitamin D deficiency in 40.3% (n=25) vs. 41.4% (n=41), and insufficiency 33.9% (n=21) vs. 34.3% (n=34) in the HCs vs. IBS groups, respectively. The odds of IBS did not differ depending on 25(OH)D status (p=0.75 for deficient, p=0.78 for insufficient), and the average plasma vitamin D concentration did not differ between IBS (mean 24.8 ng/ml) and HCs (mean 25.1 ng/ml; p=0.57). We did not find evidence of an association between plasma 25(OH)D concentration and richness, Shannon index, Simpson index or specific bacterial abundances in either HCs or the IBS group.

Keywords: irritable bowel syndrome, gastrointestinal microbiome, Vitamin D

Introduction

Irritable bowel syndrome (IBS) is one of the most common disorders of gut-brain interaction, affecting 12.0% of women and 8.6% of men worldwide (Oka et al., 2020). Currently, diagnosis is made using the symptom-based Rome Criteria (Drossman, 2017), where IBS is defined as a combination of abdominal pain and a change in the frequency or form of stool. The underlying pathophysiology of IBS may include altered central nervous system processing, low-grade local mucosal inflammation, systemic immune activation, increased intestinal permeability, intestinal hypersensitivity, diet, environmental factors, and dysbiosis (Ng et al., 2018). While one or more of these factors may contribute to IBS pathophysiology, common outcomes of IBS include decreased quality of life as well as work and productivity impairments (Frändemark et al., 2018).

A variety of interventions have focused on reducing symptoms of IBS. Findings from 2 recent systematic reviews suggest that vitamin D supplementation improves IBS symptoms such as abdominal pain, constipation, visceral sensitivity, distention, flatulence, and overall gastrointestinal symptoms among individuals with IBS (Chong et al., 2022; Huang et al., 2022). However, a recent study found no difference in the change of IBS symptom severity in the treatment group compared to those who received placebo (Williams et al., 2022). Understanding the treatment effect of vitamin D supplementation is challenging due to inter-study variations in dosing, treatment duration, lack of attention to dietary sources of vitamin D, and cohort demographics including seasonal differences in sun exposure.

Vitamin D, a steroid hormone, can be obtained from food, supplements, and sun-related synthesis (Cutolo et al., 2014; Matthews et al., 2021). Vitamin D from both diet and sun-related synthesis is biologically inert and must go through hydroxylation in the liver and the kidneys to become active. Hydroxylation in the liver results in the formation of inactive 25-hydroxycholecalciferol (abbreviated 25(OH)D). This is followed by renal hydroxylation of 25(OH)D to the physiologically active form 1,25-dihydroxycholecalciferol (abbreviated 1,25(OH)2D) (Alonso et al., 2022). Due to its longer half-life and higher plasma and serum concentration, 25(OH)D is the preferred clinical marker of vitamin D status (Alonso et al., 2022).

Many tissues, including the epithelium of the gastrointestinal tract, kidneys, endocrine glands, and immune cells possess vitamin D receptors (Bakke et al., 2018; Wang et al., 2020). In the GI tract vitamin D may affect gut health directly (e.g., reducing inflammation and permeability) or indirectly by modification of the gut microbiome (Bakke et al., 2018; Li et al., 2015; Ng et al., 2018; Yamamoto & Jorgensen, 2019). One systematic review of 10 mouse and 14 human studies (e.g., Crohn’s disease, ulcerative colitis, multiple sclerosis, and cystic fibrosis) reported a positive association between vitamin D (serum levels and supplementation) and the gut microbiome diversity (Waterhouse et al., 2019). However, the association between microbial diversity and vitamin D in persons with IBS remains to be explored (Waterhouse et al., 2019).

Based on the potential importance of vitamin D to IBS pathophysiology and treatment (Distrutti et al., 2016; Harris & Baffy, 2017; Hollister et al., 2020; Waterhouse et al., 2019), we investigated the association of plasma 25(OH)D status with microbiome composition. Based on the literature we first hypothesized that more individuals with IBS would be vitamin D deficient (25(OH)D < 20 ng/mL) compared to a healthy control comparison group. Second, we explored whether plasma 25(OH)D concentration is associated with gut microbiome characteristics (alpha and beta diversity, Firmicutes/Bacteroidetes ratio, and Lactobacillus and Bifidobacterium abundance) in individuals with IBS and healthy controls.

Methods

Participants and Setting

This retrospective comparative case–control study used plasma and stool samples originally collected from 2 National Institute of Health and National Institute of Nursing Research studies (Study 1: grant# NR 014479-03, PI Heitkemper [Jarrett et al., 2016]; Study 2: grant# NR 04101, PI Heitkemper [Kamp et al., 2021]). Both used similar methods, recruiting women with IBS and health control (HCs) women from the Seattle, Washington metropolitan area in the Pacific Northwest (PNW) through community advertisements. Participants were required to be 18–50 years old. Women in the IBS group had to have a prior medical diagnosis of IBS and meet the Rome III criteria for at least 6 months to be eligible. Women in the HC group had to have no history of functional gastrointestinal disorders or other moderate to very severe diseases/disorders. In both studies, participants with IBS and HCs were excluded from the study if they: 1) reported regular medication use defined as at least 4 days a week for IBS symptoms; 2) had a history of inflammatory bowel disease; 3) had a first-degree relative with history of colorectal cancer who was diagnosed before the age of 60; 4) had a history of abdominal surgery that used a central incision; 5) had poorly controlled mental health disorder (i.e., history of psychosis, drug or alcohol abuse, bipolar disorder); 6) reported a “red flag” symptom such as unintended weight loss of ≥10 pounds, anemia, or blood in their stool; and 7) were pregnant, breast feeding, or planning to get pregnant within the next 2 months. Furthermore, HCs were excluded if they reported current or previous IBS-like symptoms. For Study 2, participants were excluded if they had a current or recent (within the last 2 months) bacterial or viral GI infection and/or used antibiotics within the past 2 months. Timing of blood sampling controlled for menstrual cycle as this has been linked to variation in serum vitamin D levels.

In both studies, informed consent was obtained from participants and data were de-identified. For both studies, participants provided a blood sample and completed a 28-day daily diary which included information on vitamin D and multivitamin supplementation. Additionally, participants in Study 2 provided a stool sample. Participants found to have toxic 25(OH)D concentrations (n = 1; Fraser, 2021) were excluded from analysis.

Measures

Plasma 25(OH)D concentration

Archived plasma samples had been stored at −80°C (Study 1 since 2012; Study 2 since 2015) and were available for inclusion in this study. None of the samples had been thawed prior to the assay. Aliquots representing a total of 99 individuals with IBS and 62 HCs were thawed and kept on ice prior to testing at the University of Washington School of Nursing core lab. For the ELISA test targeting 25(OH)D, a commercially available kit was used (Cayman Chemical, Ann Arbor, Michigan) using their protocols. This assay detects the metabolically stable forms 25(OH)D3 and 25(OH)D2. The inter-assay reliability is 6.3% and intra-assay is 10.4%. Sensitivity is 0.5 ng/mL (range 0.19–25 ng/mL), as per the kit information. Plasma concentrations of 25(OH)D < 20 ng/mL, ≥20 to <30 ng/mL, and ≥30 ng/mL were considered as deficient, insufficient, and sufficient, respectively, as per the Endocrine Society’s vitamin D guidelines (Holick et al., 2011).

Microbiome

16S rRNA sequencing data, generated as described elsewhere (Kamp et al., 2021), were available for 62 individuals with IBS and 39 HCs who also had vitamin D data. Operational taxonomic units (OTUs) were classified at genus and phylum level. Microbiome samples with fewer than 10,000 reads were excluded, and remaining samples had a median sequencing depth of 20,335 (range: 13,501 to 35,776). OTUs appearing in two or fewer samples were excluded from beta diversity analyses. Measures of alpha diversity included species richness (rarefaction-based estimate from R package vegan), Shannon index, and Simpson index. Firmicutes and Bacteroidetes relative abundances were extracted from phylum-level profiles and the ratio was taken (F:B ratio). Bifidobacterium and Lactobacillus abundances were CLR-transformed and extracted from genus-level microbiome profiles.

Demographics

Demographic data (e.g., age, race) and disease-specific information, including IBS status and Rome III subgroup, were available from the parent studies.

Seasonality and Supplementation

The date of the blood draw was used to determine seasonality. Winter was defined as December-February; spring as March-May; summer as June-August; and fall as September-November. Subjects were considered positive for vitamin D or multivitamin supplementation, respectively, if vitamin D or multivitamin supplements were self-reported in their daily diary within 5 days prior to the blood draw; supplementation was treated as a 4-category variable (none, vitamin D only, multivitamins only, or both). Frequency of subjects self-reporting supplement use within 5 days is reported in Supplementary Table S1. Self-reporting of dosage was infrequent, so no dosage information was utilized.

Statistical Analysis

Power

With n(IBS) = 99 and n(HC) = 62 and assuming 2-tailed tests, the group comparative analysis for Aim 1 had 80% statistical power for detecting the moderate E.S.(d) > 0.46. For Aim 2, the analyses had 80% statistical power for detecting significant correlations r > 0.35 for the n(IBS) sample = 62 and r > 0.43 for the n(HC) sample = 39.

Analysis approaches

Plasma 25(OH)D concentration of IBS and HC samples were compared using independent sample t-tests for log-transformed 25(OH)D concentration. Logistic regression was used to test associations between odds of IBS and the ordered categorical variable resulting from stratification of 25(OH)D levels using established clinical thresholds. Linear regression was used to test the association between 25(OH)D levels and predetermined microbiota variables, with Wald tests to test multiple regression coefficients simultaneously as needed. Covariates included in adjusted models were age, race, household income, season of blood draw, and recent supplementation with multivitamins, vitamin D, or both. Both 25(OH)D and the microbiome features were standardized to have mean 0 and standard deviation 1 prior to regression analysis. The association was tested within each group (HC, IBS) separately to obtain within-group partial correlation and p-values, and then a regression model with an interaction between the microbiome measure and IBS status was fit to assess whether the association differed between the two groups. For beta diversity analysis, the Microbiome Regression-Based Kernel Association Test (MiRKAT) (Zhao et al., 2015) was used to assess global associations between the microbiome and 25(OH)D. The significance level was α = 0.05. No adjustment for multiple comparisons is reported because no p-values were significant prior to adjustment. Analysis was carried out using SPSS v22, Stata 16, and R 4.2.0.

Results

Participant Demographics

Participant demographics were similar between the two studies. There were a total of 62 HC and 99 IBS participants (Table 1). The mean (sd) age in years for each group was HC 28.6 (7.1) and IBS 28.7 (6.8) for Study 1, and HC 27.0 (5.5), IBS 29.2 (8.3) for Study 2. The participants were predominantly White (HC n = 12, 60.0%, IBS n = 27, 77.1% in Study 1, and HC n = 28, 66.7%, IBS n = 47, 74.6% in Study 2). Although proportions of participants with certain income levels, marital status, and education levels differ somewhat between groups defined by IBS status and parent study, consistent patterns are difficult to distinguish.

Table 1.

Demographic characteristics of study participants.

Study 1 Study 2
HC IBS HC IBS
n 20 35 42 63
Age (SD)  28.6 (7.1) 28.7 (6.8) 27.0 (5.5) 29.2 (8.3)
Race
 Asian 3 (15.0%) 2 (5.7%) 7 (16.7%) 6 (9.5%)
 Black 0 (0%) 3 (8.6%) 0 (0%) 3 (4.8%)
 White 12 (60.0%) 27 (77.1%) 28 (66.7%) 47 (74.6%)
 Any other or multiple races 5 (25.0%) 3 (8.6%) 4 (9.5%) 6 (9.5%)
 Unknown 0 (0%) 0 (0%) 3 (7.1%) 1 (1.6%)
Marital Status
 Single 13 (65.0%) 21 (60.0%) 26 (61.9%) 35 (55.6%)
 Married or Partnered 3 (15.0%) 13 (37.1%) 15 (35.7%) 26 (41.3%)
 Widowed, Divorced, or Separated 3 (15.0%) 1 (2.9%) 1 (2.4%) 2 (3.2%)
Education
 Unknown 0 (0%) 1 (2.9%) 0 (0%) 0 (0%)
 12th grade or less 1 (5%) 2 (5.7%) 4 (9.5%) 7 (11.1%)
 Vocational school, associate degree, or some college 5 (25%) 6 (17.1%) 5 (11.9%) 12 (19.0%)
 Bachelor’s degree 9 (45%) 12 (34.3%) 21 (50.0%) 29 (46%)
 Graduate degree 5 (25%) 14 (40%) 12 (28.6%) 15 (23.8%)
Income
 Unknown 3 (15%) 3 (8.6%) 2 (4.8%) 5 (7.9%)
 Less than $20,000 5 (25%) 6 (17.1%) 9 (21.4%) 12 (19.0%)
 $20,000-$49,999 4 (20%) 13 (37.1%) 13 (31%) 15 (23.8%)
 $50,000-$79,999 3 (15%) 7 (20%) 11 (26.2%) 9 (14.3%)
 $80,000-$109,999 4 (20%) 3 (8.6%) 3 (7.1%) 8 (12.7%)
 $110,000 and above 1 (5.9%) 3 (9.4%) 4 (10%) 14 (24.1%)
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Note. IBS = irritable bowel syndrome; HC = healthy controls; SD = standard deviation.

Rate of Vitamin D Deficiency

Using the Endocrine Society Practice Guidelines (Holick et al., 2011), 41.4% (n = 41) of IBS patients and 40.3% (n = 25) of HCs were vitamin D deficient (25(OH)D < 20 ng/mL), and 34.3% (n = 34) of IBS patients and 33.9% (n = 21) of HCs were vitamin D insufficient (25(OH)D ≥ 20 to <30 ng/mL). The odds of having IBS did not differ significantly between 25(OH)D groups (Table 2) in either an unadjusted analysis or after adjusting for age, race, household income, season of blood draw, and recent supplementation with multivitamins or vitamin D. Results based on associations with continuous plasma 25(OH)D agree. Average 25(OH)D among IBS subjects was 24.8 ng/mL (SD 12.0 ng/mL), whereas among HC subjects the average was 25.1 ng/mL (SD 11.7 ng/mL). In a multiple linear regression model for log-transformed 25(OH)D, we did not find associations with IBS (p = 0.57), season of blood draw (joint p = 0.95), or supplementation with multivitamins and/or vitamin D (joint p = 0.36), additionally adjusting for age, race, and household income (Figure 1; Supplementary Table S2; Supplememtary Figure S1 shows untransformed 25(OH)D).

Table 2.

Odds ratios comparing the odds of IBS in 25(OH)D insufficient (≥20 to <30 ng/mL) and deficient (<20 ng/mL) individuals to those with sufficient 25(OH)D (≥30 ng/mL). Adjusted analysis is adjusted for age, race (white vs. nonwhite), household income, season of blood draw, and recent supplementation (none, multivitamin only, vitamin D only, or both).

Model Odds Ratio  95% CI p-value
Deficient (vs. Sufficient) Unadjusted 1.14 0.50, 2.56 0.75
Adjusted 1.24 0.50, 3.07 0.65
Insufficient (vs. Sufficient) Unadjusted 1.13 0.48, 2.61 0.78
Adjusted 1.03 0.39, 2.68 0.95
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Figure 1.

Figure 1.

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Log-transformed plasma 25(OH)D concentrations by: a) IBS or healthy control status, b) season of blood draw, and c) supplementation with vitamin D and/or multivitamins within 5 days prior to blood sample. Only one HC took both forms of supplementation.

Despite insufficient statistical evidence for association, the estimates in each case are in the expected direction: we estimate that the odds of IBS is 1.24 times higher in subjects with 25(OH)D deficiency than in those with sufficient 25(OH)D after adjusting for covariates, and similarly, we estimate 4% lower 25(OH)D concentration on average in subjects with IBS compared to HCs. Seasonality estimates are also consistent with scientific expectation, particularly among HCs: the model predicts slightly lower mean 25(OH)D in winter than summer after adjusting for IBS status, supplementation, race, age, and income, and in Supplementary Table S3 and Figure 1(b), higher average 25(OH)D is observed in summer and fall than in winter and spring.

Relationship between Vitamin D Status and Microbiome Characteristics

Microbiome diversity

We do not find evidence of an association between plasma 25(OH)D concentration and richness, Shannon index, or Simpson index in either HCs or the IBS group, in unadjusted models or adjusting for seasonality and supplementation (Supplememtary Figure S2, Supplementary Table S4). The estimated direction of effect is somewhat inconsistent: in HCs, particularly in the adjusted model, our estimated partial correlation suggests that higher 25(OH)D may be associated with higher richness, whereas both other measures of microbiome diversity have estimated partial correlations near zero but with a negative direction. Similarly, PCoA plots using the Bray-Curtis dissimilarity show no clustering by 25(OH)D deficiency status (Supplememtary Figure S3), and beta diversity analysis considering weighted UniFrac, unweighted UniFrac, and Bray-Curtis dissimilarities does not reveal any global differences in the microbiome based on 25(OH)D concentration in either HCs or participants with IBS (Supplementary Table S5; omnibus p = 0.72 and p = 0.24, respectively).

F:B Ratio, Bifidobacterium Abundance, and Lactobacillus Abundance

The association between microbiome measures and plasma 25(OH)D concentrations in the IBS group and HCs are visualized in Supplememtary Figure S4, and results from linear regression analysis are presented in Supplementary Table S6. We do not find significant evidence for a linear association of plasma 25(OH)D concentration with the F:B ratio (p = 0.60 for HC, p = 0.11 for IBS), Bifidobacterium abundance (p = 0.98 for HC, p = 0.39 for IBS), or Lactobacillus abundance (p = 0.42 for HC, p = 0.29 for IBS). Although our study is underpowered to examine more flexible forms of association, we note that there is some suggestion of a nonlinear association between Bifidobacterium abundance and 25(OH)D in IBS (Supplememtary Figure S4).

Discussion

This study compared plasma 25(OH)D levels between IBS and healthy control samples in community-recruited individuals living in the PNW. After controlling for vitamin D supplementation, seasonality, age, race, menstrual cycle, and household income, we found no significant difference in plasma 25(OH)D levels between those with and without IBS. Additionally, we explored potential relationships between specific gut microbiome characteristics and plasma 25(OH)D levels. Among individuals with IBS and healthy controls, we found no significant relationships between plasma 25(OH)D and pre-specified gut microbiome diversity measures, F:B ratio, and the genera Lactobacillus and Bifidobacterium.

A systematic review of 26 studies of micronutrients and IBS included 8 that compared serum vitamin D levels in patients with IBS to healthy controls. In these 8 studies, vitamin D levels were lower in the IBS groups as compared to the control groups (Bek et al., 2022). Our study failed to reject the null hypothesis that a difference existed in plasma 25(OH)D levels between IBS and healthy control samples. Due to large confidence intervals observed, it is possible that a difference may still exist, but we were unable to detect it.

A notable observation from our study is that both IBS and healthy controls had relatively low levels of plasma 25(OH)D compared to the United States’ national average (Ganji, et al., 2012). Since our study took place in the PNW, where the latitude and high proportion of cloudy days leads to low levels of sun exposure a large part of the year, we controlled for seasonality in our analytic plan. Interestingly, approximately 20% of participants in both parent studies reported historical vitamin supplementation, likely suggesting that a subgroup of participants was aware of the risk for insufficient vitamin D or were being advised to take vitamin D supplements. Yet, despite vitamin supplementation, levels of plasma 25(OH)D were overall below the recommended guidelines (Holick et al., 2011). Alternatively, this could reflect long-term storage of specimens at −80°C before assays were conducted.

The literature on the relationship of vitamin D to microbiome characteristics is limited and inconsistent. This is due in part to small sample sizes in clinical trials and heterogeneity in dosing and treatment duration, as well as conditions studied. A recent study of postmenopausal women in China (60% had plasma 25(OH)D levels above 20 ng/mL) found that those with higher vitamin D levels had greater alpha diversity as compared to those with low vitamin D levels (25(OH)D levels <20 ng/mL) (Gong et al., 2022). Higher vitamin D serum and plasma levels have been shown to promote positive, albeit subtle, changes in the gut microbiota in other conditions such as inflammatory bowel disease (e.g., increased microbial diversity, increased butyrate-producing bacteria, and increased serum antimicrobial peptide cathelicidin) (Battistini et al., 2020). Lower levels of vitamin D have also been shown to affect the microbiota in inflammatory bowel disease (e.g., decreased Lactobacillus and increased Proteobacteria) (Battistini et al., 2020). However, in the current study we did not find global associations, i.e., alpha or beta diversity, of microbiome composition with plasma 25(OH)D, nor did we find an association of beneficial bacterial species (Lactobacilli and Bifidobacterium) with plasma 25(OH)D concentration in either healthy control or IBS groups. Nonetheless, the relationship of vitamin D to the gut microbiome is likely bidirectional, at least in some conditions. For example, there is evidence that intestinal bacteria are involved in steroid metabolism (Szaleniec et al., 2018; Wu, Yoon, et al., 2015). Additionally, studies in knockout mouse models show that depletion of vitamin D receptors in the gut epithelium results in microbial composition alterations (Wu et al., 2015). Thus, future studies should evaluate possible bidirectional pathways in which vitamin D and the gut microbiome interact.

Our study adds to the literature by highlighting a lack of relationship between plasma 25(OH)D and IBS status when accounting for supplementation and seasonality. The present study has several limitations. First, we did not collect information about dietary sources of vitamin D or time outdoors which could, along with supplementation and seasonality, affect vitamin D levels. Other potential confounders that were not available in our data included dietary prebiotics (Singh et al., 2017) and polyphenols. Second, we tested 25(OH)D using an immunoassay instead of LC-MS/MS which is now considered the gold standard test for vitamin D (Zelzer et al., 2022). Finally, our study was underpowered to detect associations between 25(OH)D and the microbiome due to both modest sample sizes and the high rate of vitamin D deficiency/insufficiency in healthy controls in this PNW sample, which restricts the possible magnitude of difference in 25(OH)D between groups. Further examination of the relationship of vitamin D, microbiome, and IBS is needed with larger sample sizes and possibly more diverse geographical representation to ensure adequate power.

Conclusion

Although most of the evidence in the literature suggests that vitamin D deficiency and supplementation can influence the composition of the microbiome and may be a factor in IBS, we do not see such an association in this population of women with IBS and healthy women in the Pacific Northwest.

Supplemental Material

Supplemental Material - Exploring the Role of Vitamin D and the Gut Microbiome: A Cross-Sectional Study of Individuals with Irritable Bowel Syndrome and Healthy Controls
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Supplemental Material for Exploring the Role of Vitamin D and the Gut Microbiome: A Cross-Sectional Study of Individuals with Irritable Bowel Syndrome and Healthy Controls by Sarah W. Matthews, Anna Plantinga, Robert Burr, Kevin C. Cain, Tor Savidge, Kendra Kamp, and Margaret M. Heitkemper in Biological Research for Nursing

Acknowledgments

Stephanie Binick, DNP, APRN, FNP-BC, Faculty at University of Washington, is acknowledged for her contribution to writing and editing of the manuscript. Ernie Tolentino, Senior Scientist at University of Washington, is acknowledged for his contribution to the data analysis in the manuscript.

Authors’ contribution: Matthews, S contributed to conception and design contributed to interpretation drafted manuscript critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Plantinga, A contributed to conception and design contributed to analysis and interpretation drafted manuscript critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Burr, R contributed to conception and design contributed to acquisition and analysis critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Cain, K contributed to conception and design contributed to acquisition and analysis critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Savidge, T contributed to analysis and interpretation critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Kamp, K contributed to conception and design contributed to acquisition, analysis, and interpretation drafted manuscript critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy Heitkemper, M contributed to conception and design contributed to acquisition, analysis, and interpretation drafted manuscript critically revised manuscript gave final approval agrees to be accountable for all aspects of work ensuring integrity and accuracy

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Institutes of Health (Grant Numbers R01NR014479 and R01NR001094), Sigma Theta Tau International Psi at Large chapter, and the University of Washington School of Nursing Office of Nursing Rese. Kendra J Kamp was funded, in part, by the National Institutes of Health, National Institute of Nursing Research (Grant Number K23NR020044). Tor Savidge was funded, in part, by the National Institute of Nursing Research (Grant Numbers NINR R01-NR013497; NIDDK P30-DK56338 and R01DK130517).

Supplemental Material: Supplemental material for this article is available online.

ORCID iDs

Sarah W. Matthews https://orcid.org/0000-0002-2840-642X

Kendra Kamp https://orcid.org/0000-0002-7753-3564

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